Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors

Abstract

Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.is a neurodevelopment disorder that affects girls, with an incidence of 1:10,000 (1). RTT individuals develop typically until 6-18 mo, when neurological symptoms begin, including intellectual disability, autistic features, deficits in motor control and sensory perception, breathing irregularities, and epilepsy disorders (2). Loss-of-function mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MECP2) occur in 95% of RTT individuals (3), and Mecp2-deficient mice recapitulate several neurological features of RTT, including impaired hippocampal-dependent learning and memory (4).Long-term potentiation (LTP), a cellular correlate of learning and memory (5), is impaired at hippocampal CA1 excitatory synapses of symptomatic Mecp2 knockout (KO) mice (6, 7), mice that express nonfunctional MeCP2 (Mecp2 308 ) (8), and mice with a STOP codon before Mecp2 exon 3 (Mecp2 stop ) (9, 10). LTP is also impaired at excitatory synapses of layers II/III and V in the primary somatosensory cortex of Mecp2 KO mice (11, 12) and Mecp2 308 mice (8) and in cortico-lateral amygdala synapses of Mecp2 KO mice (13). Several mechanisms have been proposed to underlie these deficits, including altered composition of synaptic NMDA receptors, sparse connectivity through weak synapses, and LTP saturation (6,10,11).Despite the consensus that LTP is impaired in the absence of MeCP2, the underlying cellular and synaptic mechanisms remain unclear. It is well established that long-term plasticity of excitatory synaptic transmission is critically determined by activity-dependent insertion and removal of AMPA receptors (AMPARs) to and from the postsynaptic membrane (14). Here, we assessed the synaptic strength of naïve hippocampal CA1 synapses in Mecp2 KO mice and revisited the issue of their LTP...

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

“…Of relevance to RTT and consistent with in vivo and in vitro observations (Belichenko et al, 1994; Chao et al, 2007; Chapleau et al, 2009a, 2012), cultured hippocampal neurons from Mecp2 KO mice have a lower spine density than those from WT mice (Figures 4A,B; WT = 4.25 ± 0.28 spines/10 μm, total dendritic length 888.14 μm; Mecp2 = 3.13 ± 0.3 spines/10 μm, total length 1377.83 μm; K-S test: p = 0.0054). However, the volume of individual spines is larger in Mecp2 KO neurons than in WT neurons (Figures 4A,C; WT = 0.18 ± 0.02 μm 3 ; Mecp2 = 0.21 ± 0.01 μm 3 ; p = 0.002), as observed in CA1 pyramidal neurons of symptomatic Mecp2 KO mice and consistent with stronger excitatory synapses (Li et al, 2016). …”

Ventral hippocampal projections to the medial prefrontal cortex regulate social memory

“…However, mPFC slices from Mecp2 KO mice showed only a short-term enhancement of the spatiotemporal spread of VSD signals, which quickly decayed back to baseline levels (n=9 slices from 5 mice, p=0.2705; Student's paired t-test; Figure S2). These data demonstrate an impairment of LTP at excitatory vHIP-mPFC synapses, similar to that previously reported at CA3-CA1 synapses in hippocampal slices of Mecp2 KO mice (Li et al, 2016).…”

Autism spectrum disorder: neuropathology and animal models

“…These changes are apparently due to a delay in development and synapse formation in neurons resulting from Mecp2 haploinsufficiency [115, 330], which are abnormalities in development that do not recover with age. MeCp2 deficiency results in reduction of glutamatergic synapses [63] and increased basal levels of AMPA, indicating a failure in activity-dependent synaptic trafficking of the receptor [217]. Mecp2 -deficient spines also fail to increase in volume upon induction of long-term potentiation, indicating the loss of activity-dependent synaptic plasticity [217].…”

“…MeCp2 deficiency results in reduction of glutamatergic synapses [63] and increased basal levels of AMPA, indicating a failure in activity-dependent synaptic trafficking of the receptor [217]. Mecp2 -deficient spines also fail to increase in volume upon induction of long-term potentiation, indicating the loss of activity-dependent synaptic plasticity [217]. …”